ABSTRACT The overall goal of this study is to characterize sex differences in neural systems underlying Alzheimer?s disease (AD) progression, and to test a cerebrovascular (CV) model explaining these sex differences. This study takes advantage of a unique opportunity to recruit from two longitudinal R01 on pre-clinical AD to achieve a well-characterized cohort of older adults with identical PET (amyloid and tau) and 7T MR imaging protocols. Recently, we have found that cognitively normal women and men with high amyloid burden show different patterns of hippocampal connectivity. The different patterns of connectivity between women and men are similar to what we and others have found in relation to cerebral small vessel disease (SVD). Women with high amyloid burden and Individuals with high SVD burden share similar patterns: higher local hippocampal-medial temporal lobe (MTL) connectivity and lower distant hippocampal-prefrontal connectivity. Further, recent data have shown that women with high amyloid burden also have higher entorhinal cortical tau deposition and faster cognitive decline, than men. These converging findings point to a CV mechanism, particularly cerebral SVD, that is underlying the faster progression from amyloid positivity to neurodegeneration, and subsequent cognitive decline in women. Using advanced 7T imaging techniques, e.g., Time of Flight angiography imaging and susceptibility weighted imaging, this study is able to visualize both the arteriolar anatomy and the venular anatomy. A new 3D vein segmentation algorithm BrainVein is developed and validated in this study, which allows for a faster (compared to the traditional manual tracing method), more reliable and accurate segmentation of small veins. Besides the traditional markers of SVD (e.g., white matter hyperintensities -WMH), this study will have novel morphological markers of the arterioles and venules including Arteriolar Tortuosity Index (ATI), Venular Tortuosity Index (VTI), Venular Branching Pattern (VBP), and Venular Luminal Variability Index (VLI). These novel markers represent specific, early and dynamic features of cerebral SVD and are also modifiable through lifestyle changes and medical management. With this well-characterized cohort, in Aim 1 we will identify SVD markers that differ between women and men, and characterize the associations between SVD markers with AD risk factors. In Aim 2 we characterize sex differences in amyloid- and tau-related functional changes, and in Aim 3, we will identify specific SVD markers that can explain sex differences observed in Aim 2. Results from these aims can inform the sex-specific prevention and treatment strategy of AD.